Alcoholism

John C. M. Brust

INTRODUCTION

In the United States, 7% of all adults and 19% of adolescents are “problem drinkers”: psychically or physically dependent on ethanol or, even if abstinent most of the time, likely to get into trouble when they drink. Ethanol-related deaths exceed 100,000 each year, accounting for 5% of all deaths in the United States. The devastation is direct (from intoxication, addiction, and withdrawal) or indirect (from nutritional deficiency or other ethanol-related diseases).

ACUTE ETHANOL SYNDROMES

INTOXICATION

Ethanol acts at many levels of the neuraxis. Although specific ethanol receptors comparable to opioid receptors do not appear to exist, ethanol interacts directly with membrane proteins of a number of neurotransmitter systems, and much of its actions depend on facilitation at inhibitory γ-aminobutyric acid (GABA) receptors and inhibition at excitatory glutamate receptors.

To obtain a mildly intoxicating blood ethanol concentration (BEC) of 100 mg/dL, a 70-kg person must drink about 50 g (2 oz) of 100% ethanol. Following zero-order kinetics, ethanol is metabolized at about 70 to 150 mg/kg of body weight per hour, with a fall in BEC of 10 to 25 mg/dL/h. Thus, most adults require 6 hours to metabolize a 50-g dose, and the ingestion of only 8 g of additional ethanol per hour would maintain the BEC at 100 mg/dL.

Symptoms and signs of acute ethanol intoxication are a result of cerebral depression, possibly at first of the reticular formation with cerebral disinhibition and later of the cerebral cortex itself. Manifestations depend not only on the BEC but also on the rate of climb and the person’s tolerance, which is related less to increased metabolism than to poorly understood adaptive changes in the brain. At any BEC, intoxication is more severe when the level is rising than when it is falling, when the level is reached rapidly, and when the level has only recently been achieved. A single BEC determination therefore is not a reliable indicator of drunkenness, and the correlations of Table 126.1 are broad generalizations. Death from respiratory paralysis may occur with a BEC of 400 mg/dL, and survival may occur at 700 mg/dL; a level of 500 mg/dL would be fatal in 50% of individuals.

Low to moderate BECs cause slow saccadic eye movements and interrupted jerky pursuit movements that may impair visual acuity. Esophoria and exophoria cause diplopia. With a BEC of 150 to 250 mg/dL, there is increased electroencephalography (EEG) beta activity (“beta buzz”); higher BECs cause EEG slowing. During sleep, suppression of the REM stage is followed by REM rebound after a few hours.

TABLE 126.1 Correlation of Symptoms with Blood Ethanol Concentration

BEC	Symptoms
50-150 mg/dL	Euphoria or dysphoria, shyness or expansiveness, friendliness or argumentativeness Impaired concentration, judgment, and sexual inhibitions
150-250 mg/dL	Slurred speech and ataxic gait, diplopia, nausea, tachycardia, drowsiness, or labile mood with sudden bursts of anger or antisocial acts
300 mg/dL	Stupor alternating with combativeness or incoherent speech, heavy breathing, vomiting
400 mg/dL	Coma
500 mg/dL	Respiratory paralysis
BEC, blood ethanol concentration.

The term pathologic intoxication refers to sudden extreme excitement with irrational or violent behavior after even small doses of ethanol. Episodes are said to last for minutes or hours, followed by sleep and, on awakening, amnesia for the events that took place. Delusions, hallucinations, and homicide may occur during bouts of pathologic intoxication. Some cases might be psychological dissociative reactions; others may be owing to the kind of paradoxic excitation that sometimes follows barbiturate administration. These syndromes are more likely to occur in younger people that have had little prior exposure to alcohol.

The term alcoholic blackout refers to amnesia for periods of intoxication, sometimes lasting several hours, even though consciousness at the time did not seem to be disturbed. Although sometimes considered a sign of physiologic dependence, blackouts also occur in occasional drinkers. The amnesia is a direct effect of ethanol on memory encoding.

Acute ethanol poisoning causes more than 1,000 deaths each year in the United States. In stuporous alcoholic patients, subdural hematoma, meningitis, and hypoglycemia are important diagnostic considerations, but it is equally important to remember that ethanol intoxication alone can be fatal.

Blood ethanol causes a rise of blood osmolality, about 22 mOsm/L for every 100 mg/dL of ethanol; however, there are no transmembrane shifts of water, and the hyperosmolarity does not cause symptoms.
Ethanol overdose should be considered in any comatose patient whose serum osmolarity is higher than predicted by calculation of the sum of serum sodium, glucose, and urea.

TABLE 126.2 Treatment of Acute Ethanol Intoxication

For Obstreperous or Violent Patients

Isolation, calming environment, and reassurance—avoid sedatives.

Close observation

For Stuporous or Comatose Patients

If hypoventilation, artificial respiration in an ICU

If serum glucose in doubt, intravenous 50% glucose with parenteral thiamine 100 mg

Careful monitoring of blood pressure; correction of hypovolemia or acid-base imbalance

Consider hemodialysis if patient is severely acidotic, deeply comatose, or apneic.

Avoid emetics or gastric lavage.

Avoid analeptics.

Do not forget other possible causes of coma in an alcoholic.

ICU, intensive care unit.

Patients stuporous or comatose from ethanol intoxication are generally managed similarly to those poisoned by other depressant drugs (Table 126.2). Death comes from respiratory depression, and mechanical ventilation in an intensive care unit is the mainstay of treatment. Hypovolemia, acid-base or electrolyte imbalance, and abnormal temperature require attention, and if there is any uncertainty about the blood glucose level, 50% glucose is given intravenously, along with parenteral thiamine. Because ethanol is rapidly absorbed, gastric lavage does not help unless other drugs have been ingested. In obstreperous or violent patients, sedatives (including benzodiazepines and dopamine-blocking agents) should be used with caution because they may push patients into stupor and respiratory depression. Patients being addressed may appear alert but then lapse into stupor or coma when stimuli are decreased.

In a nonhabitual drinker, a BEC of 400 mg/dL can take 20 hours to return to zero. The only practical agent that might accelerate ethanol metabolism and elimination is fructose, but this causes gastrointestinal upset, lactic acidosis, and osmotic diuresis. Hemodialysis or peritoneal dialysis can be used for BECs greater than 600 mg/dL; for severe acidosis; for concurrent ingestion of methanol, ethylene glycol, or other dialyzable drugs; or for severely intoxicated children. Analeptic agents such as ethamivan, caffeine, or amphetamine have no useful role and can cause seizures and cardiac arrhythmia. Although patients are often depleted of magnesium, administration of magnesium sulfate may further depress the sensorium in intoxicated patients. Anecdotal reports describe temporary reversal of ethanol intoxication with the mu-opioid antagonist naloxone.

ETHANOL-DRUG INTERACTIONS

The combination of ethanol with other drugs, often in suicide attempts, causes 2,500 deaths annually or 13% of all drug-related fatalities. Ethanol is often taken with marijuana, barbiturates, opioids, cocaine, hallucinogens, and inhalants—with varying interactions. Alcoholics often abuse barbiturates, and although ethanol and barbiturates are cross-tolerant, each lowers the lethal dose of the other when they are taken in combination. Ethanol with chloral hydrate (“Mickey Finn”) may be especially dangerous.

Impaired judgment and respiratory depression are also hazards when ethanol is combined with hypnotics, such as methaqualone (Quaalude), sedating antihistamines, antipsychotic agents, and benzodiazepines. Hypnotic drugs with long half-lives may cause potentially dangerous incoordination when ethanol is consumed the following day.

The cross-tolerance of ethanol with general anesthetics raises the threshold to sleep induction, but synergistic interaction then increases the depth and length of the anesthetic stage reached. Tricyclic antidepressants do not have a consistent effect; desipramine antagonizes the effects of ethanol and amitriptyline potentiates them. Ethanol and morphine, repeatedly used, can increase each other’s potency, and methadone addicts not only frequently become alcoholic but also then develop a characteristic encephalopathy. Death has followed ethanol taken with propoxyphene. A mild reaction resembling that caused by disulfiram occurs when patients combine ethanol with sulfonylureas such as tolbutamide or with some antibiotics, including chloramphenicol, griseofulvin, isoniazid, metronidazole, and quinacrine.

ETHANOL WITHDRAWAL

The term hangover refers to the headache, nausea, vomiting, malaise, nervousness, tremulousness, and sweating that can occur in anyone after brief but excessive drinking. Hangover does not imply ethanol dependence, but ethanol withdrawal does imply dependence and encompasses several disorders (Table 126.3), which may occur alone or in combination after reduction or cessation of drinking. Severity depends on the length and degree of a particular binge. Withdrawal syndromes are particularly common during hospitalization and can be exacerbated by concurrent illness.

Tremulousness, the most common ethanol withdrawal symptom, usually appears in the morning after several days of drinking. It is usually promptly relieved by ethanol, but if drinking cannot continue, tremor becomes more intense, with insomnia, easy startling, agitation, facial and conjunctival flushing, sweating, anorexia, nausea, retching, weakness, tachypnea, tachycardia, and systolic hypertension. Except for inattentiveness and inability to fully recall the events that occurred during the binge, mentation is usually intact. In some patients, tremulousness can persist for weeks or longer.

Perceptual disturbances, with variable insight, occur in about 25% of ethanol-dependent patients and include nightmares, illusions, and hallucinations, which are most often visual but may be auditory, tactile, olfactory, or a combination of these. Imagery includes insects, animals, or people. Hallucinations are usually fragmentary,
lasting minutes at a time for several days. Sometimes, however, auditory hallucinations of threatening content last much longer and may even progress to a persistent state of auditory hallucinosis with paranoid delusions requiring care in a mental hospital. Repeated bouts of acute auditory hallucinosis may predispose to the chronic form.

TABLE 126.3 Ethanol Withdrawal Syndromes

Early (<48 hours after last drink)

Tremulousness

Hallucinosis

Seizures

Late (>48 hours after last drink)

Delirium tremens

Ethanol can precipitate seizures in any epileptic; seizures usually occur the morning after weekend or even single-day drinking rather than during inebriation. Alcohol-related seizures affecting alcoholics not otherwise epileptic have traditionally been considered a withdrawal phenomenon, usually occurring within 48 hours of the last drink in persons who have abused ethanol chronically or in binges for months or years. The minimal duration of drinking sufficient to cause seizures is uncertain, but the risk is dose-related, beginning at only 50-g absolute ethanol daily. (In the United States, a “standard drink” usually means 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80 proof spirits, each containing 14 g of absolute ethanol.) Seizures usually occur singly or in a brief cluster; status epilepticus is infrequent. Focal features are present in 25% and do not consistently correlate with evidence of previous head injury or other structural cerebral pathology. Alcohol seizures sometimes accompany tremulousness or hallucinosis, but they may occur in otherwise asymptomatic individuals. Their frequent appearance during active drinking or after more than 1 week of abstinence is consistent with mechanisms other than withdrawal per se.

The diagnosis of alcohol-related seizures depends on an accurate history and exclusion of other cerebral lesions. Workup should include brain computed tomography (CT) or magnetic resonance imaging (MRI) and consideration of lumbar puncture. Alcohol withdrawal can trigger new-onset seizures in patients with intracranial hemorrhage, central nervous system (CNS) infection, or brain neoplasm. Fewer than 10% of patients with alcoholrelated seizures have spontaneous EEG abnormalities, compared with 50% of those with idiopathic epilepsy.

Transient parkinsonism during alcohol withdrawal is described in older patients. Transient chorea and dystonia are described in younger patients.

In contrast to tremor, hallucinosis, or seizures, which usually occur early and within 48 hours of abstinence, delirium tremens usually begins from 48 to 72 hours after the last drink. Patients with delirium tremens are often hospitalized for other reasons. Delirium tremens may follow withdrawal seizures either before the postictal period has cleared or after 1 or 2 asymptomatic days, but when seizures occur during a bout of delirium tremens, some other diagnosis (e.g., meningitis) should be considered.

Symptoms of delirium tremens typically begin and end abruptly, lasting from hours to a few days. There may be alternating periods of confusion and lucidity. Infrequently, relapses may prolong the disorder for a few weeks. Patients are typically agitated, inattentive, and grossly tremulous, with fever, tachycardia, and profuse sweating. They pick at the bed clothes or stare wildly about and intermittently shout at or try to fend off hallucinated people or objects. “Quiet” delirium is infrequent. Mortality is as high as 15%; death is usually owing to other diseases (e.g., pneumonia or cirrhosis), but it may be attributed to unexplained shock or lack of response to therapy or have no apparent cause.

The pathophysiologic basis of ethanol withdrawal in its several forms is probably a combination of glutamate receptor upregulation and GABA receptor downregulation. Neuronal excitotoxicity during withdrawal could then set the stage for a kindling pattern of repeated withdrawal episodes, further excitotoxicity, a permanently lowered seizure threshold, and the occurrence of seizures temporally independent of withdrawal.

Treatment of ethanol withdrawal includes prevention or reduction of early symptoms, prevention of delirium tremens, and management of delirium tremens after it starts (Table 126.4). Benzodiazepines, which have cross-tolerance with ethanol, are appropriately given to recently abstinent alcoholics or those with mild early withdrawal symptoms. Lorazepam (Ativan) 2 to 4 mg every 4 hours is a reasonable starting agent and dose. It is important to adjust the dose to symptom response, level of consciousness, and respiratory status after initiating therapy. A loading dose may cause symptoms of mild intoxication (calming, dysarthria, ataxia, fine nystagmus); dosage can then be adjusted to avoid both intoxication and tremulousness, and after 1 or 2 days, it can be gradually tapered, with reinstitution should withdrawal symptoms reappear.

Compared to fixed dose schedules, symptom-triggered pharmacotherapy more effectively decreases the likelihood of progression to delirium tremens and is less likely to result in sedative accumulation. Among standard protocols for symptom-triggered therapy, the Clinical Institute for Withdrawal Assessment for Alcohol (CIWA-Ar) scale assesses at regular intervals vital signs, nausea/vomiting, tremor, paroxysmal sweating, anxiety, agitation, tactile, visual or auditory disturbances, headache, and orientation/clouding of consciousness.

β-Adrenergic blockers such as propranolol and α-2 agonists such as clonidine or dexmedetomidine are helpful as adjunctive therapy to help control symptoms of sympathetic overdrive, but they are not cross-tolerant with alcohol and have reportedly triggered hallucinosis. Phenobarbital, which has a different GABAergic mechanism of action than benzodiazepines, has also been used as add-on treatment.

TABLE 126.4 Treatment of Ethanol Withdrawal

Prevention or Reduction of Early Symptoms

Lorazepam 1-4 mg PO or IV; diazepam 5-20 mg; or chlordiazepoxide 25-100 mg repeated hourly until sedation or mild intoxication; successive daily doses tapered with resumption of higher dose if withdrawal symptoms recur

Thiamine 100 mg and multivitamins IM or IV

Magnesium, potassium, and calcium replacement as needed

Delirium Tremens

Lorazepam 2-4 mg IV or IM or diazepam 10 mg IV, repeated every 5-15 min until calming; maintenance dose every 1-4 h p.r.n.

If refractory to benzodiazepines, phenobarbital 260 mg IV repeated in 30 min p.r.n.

If refractory to phenobarbital, propofol 25-100 µg/kg/min, with endotracheal intubation and repeated doses to produce general anesthesia

Careful attention to fluid and electrolyte balance; several liters of saline per day, or even pressors, may be needed.

Cooling blanket for high fever

Prevent or correct hypoglycemia.

Thiamine and multivitamin replacement

Consider coexisting illness (e.g., liver failure, pancreatitis, meningitis, subdural hematoma).

PO, by mouth; IV, intravenous; IM, intramuscular; p.r.n., as needed.

Numerous anticonvulsants, especially those with GABAergic actions, have been subjected to randomized trials comparing them to benzodiazepine or placebo. A Cochrane review of 56 such trials concluded that evidence was insufficient to recommend their use. Similar conclusions were reached in Cochrane reviews of baclofen or γ-hydroxybutyric acid compared to benzodiazepines in the treatment of alcohol withdrawal.

Intravenous parenteral ethanol solutions have been used to treat delirium tremens. Treating with parenteral ethanol has the disadvantage of a low therapeutic index, and because ethanol is directly toxic to many organs, it should be avoided during hospitalization, even though most patients resume drinking on discharge. Haloperidol and phenothiazines are less likely to prevent hallucinosis or delirium tremens than drugs cross-tolerant with ethanol, and they can lower seizure threshold, prolong the QT interval, cause hypotension, and impair thermoregulation. They are appropriately considered in patients whose only symptoms are hallucinations or in whom hallucinations have outlasted other withdrawal symptoms.

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